Candidate: The author is Chief Resident in pediatric neurology at New York Hospital-Cornell Medical Center with research training in developmental neuro-science. This award will prepare the author for a career in academic medicine as an independent investigator in developmental neurology. Proposal: Recent evidence suggests that neurotransmitter phenotypic expression is remarkably mutable. This study seeks to define the extracellular factors and intracellular processes through which sympathetic neurons regulate multiple transmitter phenotypes. The specific aims are to define mechanisms through which presynaptic neurons, the central nervous system and target organ regulate peptide and catecholamine traits, determine the role of specific messenger RNA (mRNA) in modulation and expression of catecholamine enzyme, tyrosine hydroxylase (TH), and examine the roles of neurite outgrowth and extracellular factors in initial embryonic phenotypic expression. The superior cervical sympathetic ganglion, serving as a model system of the multiple transmitter neuron, will be assayed for markers of catecholamine (TH) and peptide (Substance P, SP) phenotypes in adults and neonates in vivo and embryos in vitro. The effects of long term deafferentation on ganglion TH and SP will be defined to examine chronic regulatory mechanims during maturity and ontogeny. The regulation of transmitter trait development by central synapses and Nerve Growth Factor will also be examined. The specific role of mRNA in TH modulation and expression during maturity and ontogeny, will be defined after altering extracellular regulatory factors. The rigorous conditions of tissue culture will permit analysis of cellular and molecular mechanisms in initial phenotypic expression. Characterization of the extracellular factors regulating phenotypic plasticity may lead to therapeutic interventions which can alter deranged neurologic function and, thus, alleviate symptoms of neural tube dysgenesis, hereditary ataxias and dystonias and cerebral palsy. Elucidation of molecular genetic mechanisms of phenotypic expression may suggest new approaches to degenerative processes such as the spinal muscular atrophies, Huntington's chorea and lysosomal storage disease. Environment: The Laboratory of Developmental Neurology is actively examining classical and peptide neurotransmitter plasticity during development and maturity, in vivo and in vitro.